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1.
iScience ; 12: 270-279, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30716700

RESUMO

Congenital microcephaly occurs in utero during Zika virus (ZIKV) infection. The single-gene disorder, Majewski osteodysplastic primordial dwarfism type II (MOPDII), also leads to microcephaly and is concomitant with a decrease in the centrosomal protein, pericentrin (PCNT). This protein is a known contributor of mitotic spindle misorientation and ultimately, microcephaly. Similar to MOPDII, either viral infection or interferon (IFN)-α exposure reduced PCNT levels at the mitotic spindle poles. We unexpectedly found that infection of cells with any one of a diverse set of viruses, such as ZIKV, dengue virus, cytomegalovirus, influenza A virus, or hepatitis B virus, or treatment of cells with the anti-viral cytokine, IFN-α, produced mitotic spindle misorientation. These findings demonstrate a related mechanism for the development of microcephaly in viral infection, the host's antiviral IFN response, and primordial dwarfism.

2.
Viruses ; 6(5): 2155-85, 2014 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-24859341

RESUMO

Viruses use different strategies to overcome the host defense system. Recent studies have shown that viruses can induce DNA damage response (DDR). Many of these viruses use DDR signaling to benefit their replication, while other viruses block or inactivate DDR signaling. This review focuses on the effects of DDR and DNA repair on human cytomegalovirus (HCMV) replication. Here, we review the DDR induced by HCMV infection and its similarities and differences to DDR induced by other viruses. As DDR signaling pathways are critical for the replication of many viruses, blocking these pathways may represent novel therapeutic opportunities for the treatment of certain infectious diseases. Lastly, future perspectives in the field are discussed.


Assuntos
Citomegalovirus/fisiologia , Dano ao DNA , Resposta SOS em Genética , Replicação Viral , Reparo do DNA , Humanos
3.
J Virol ; 86(10): 5660-73, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22438545

RESUMO

Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics.


Assuntos
Infecções por Citomegalovirus/virologia , Citomegalovirus/genética , DNA Polimerase Dirigida por DNA/genética , Proteínas Imediatamente Precoces/genética , Interferência de RNA , Transativadores/genética , Proteínas Virais/genética , Replicação Viral , Linhagem Celular , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/metabolismo , Dano ao DNA , DNA Polimerase Dirigida por DNA/metabolismo , Regulação para Baixo , Regulação Viral da Expressão Gênica , Humanos , Proteínas Imediatamente Precoces/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína da Leucemia Promielocítica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Virais/metabolismo
4.
Cell Death Differ ; 18(3): 452-64, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20885445

RESUMO

The anti-apoptotic Bcl-2 protein, which confers oncogenic transformation and drug resistance in most human cancers, including breast cancer, has recently been shown to effectively counteract autophagy by directly targeting Beclin1, an essential autophagy mediator and tumor suppressor. However, it remains unknown whether autophagy inhibition contributes to Bcl-2-mediated oncogenesis. Here, by using a loss-of-function mutagenesis study, we show that Bcl-2-mediated antagonism of autophagy has a critical role in enhancing the tumorigenic properties of MCF7 breast cancer cells independent of its anti-apoptosis activity. A Bcl-2 mutant defective in apoptosis inhibition but competent for autophagy suppression promotes MCF7 breast cancer cell growth in vitro and in vivo as efficiently as wild-type Bcl-2. The growth-promoting activity of this Bcl-2 mutant is strongly correlated with its suppression of Beclin1-dependent autophagy, leading to sustained p62 expression and increased DNA damage in xenograft tumors, which may directly contribute to tumorigenesis. Thus, the anti-autophagic property of Bcl-2 is a key feature of Bcl-2-mediated oncogenesis and may in some contexts, serve as an attractive target for breast and other cancer therapies.


Assuntos
Apoptose , Autofagia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Regulação para Baixo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Neoplasias da Mama/ultraestrutura , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Dano ao DNA , Feminino , Proteínas de Choque Térmico/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Proteínas Mutantes/metabolismo , Células NIH 3T3 , Ligação Proteica , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas c-bcl-2/química , Proteína Sequestossoma-1 , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
PLoS Pathog ; 3(12): e174, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18069888

RESUMO

Upon viral infection, cells undergo apoptosis as a defense against viral replication. Viruses, in turn, have evolved elaborate mechanisms to subvert apoptotic processes. Here, we report that a novel viral mitochondrial anti-apoptotic protein (vMAP) of murine gamma-herpesvirus 68 (gammaHV-68) interacts with Bcl-2 and voltage-dependent anion channel 1 (VDAC1) in a genetically separable manner. The N-terminal region of vMAP interacted with Bcl-2, and this interaction markedly increased not only Bcl-2 recruitment to mitochondria but also its avidity for BH3-only pro-apoptotic proteins, thereby suppressing Bax mitochondrial translocation and activation. In addition, the central and C-terminal hydrophobic regions of vMAP interacted with VDAC1. Consequently, these interactions resulted in the effective inhibition of cytochrome c release, leading to the comprehensive inhibition of mitochondrion-mediated apoptosis. Finally, vMAP gene was required for efficient gammaHV-68 lytic replication in normal cells, but not in mitochondrial apoptosis-deficient cells. These results demonstrate that gammaHV-68 vMAP independently targets two important regulators of mitochondrial apoptosis-mediated intracellular innate immunity, allowing efficient viral lytic replication.


Assuntos
Apoptose , Gammaherpesvirinae/metabolismo , Mitocôndrias/metabolismo , Proteínas Virais/metabolismo , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Chlorocebus aethiops , Gammaherpesvirinae/genética , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Mitocôndrias/patologia , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Proteínas Virais/genética , Replicação Viral , Canal de Ânion 1 Dependente de Voltagem/genética , Leveduras/genética , Leveduras/metabolismo
6.
J Gerontol A Biol Sci Med Sci ; 57(7): B270-8, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12084797

RESUMO

The purpose of this study was to test whether heterozygotes of juvenile visceral steatosis mice, a model for systemic carnitine deficiency, may develop age-associated cardiomyopathy. Tissue morphological observations were carried out by light and electron microscopy to compare the heterozygous and age-matched control mice at periods of 1 and 2 years. Possible effects of the pathological mutation on lipid and glucose levels was also evaluated in humans and mice. Except mild increases in serum cholesterol levels in male heterozygous mice and humans, no changes were found in other factors, indicating that none of the confounding factors seems to be profound. Results demonstrated that heterozygous mice had larger left ventriclular myocyte diameters than the control mice. Morphological changes in cardiac muscles by electron microscopy revealed age-associated changes of lipid deposition and abnormal mitochondria in heterozygous mice. Two out of 60 heterozygous cohort and one out of nine heterozygous trim-kill mice had cardiac hypertrophy at ages older than 2 years. The present study and our previous work suggest that the carrier state of OCTN2 pathological mutations might be a risk factor for age-associated cardiomyopathy.


Assuntos
Envelhecimento , Cardiomiopatias/etiologia , Carnitina/metabolismo , Proteínas de Transporte/genética , Proteínas de Membrana/genética , Mutação , Proteínas de Transporte de Cátions Orgânicos , Adulto , Animais , Feminino , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Pessoa de Meia-Idade , Oxirredução , Membro 5 da Família 22 de Carreadores de Soluto , Taxa de Sobrevida
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